1. Field of the Invention
The present invention is generally related to the field of medical diagnostics for verifying the location of a medical device in a patient. More particularly, the present invention relates to the use of an indicator substance which is acted upon, either directly or indirectly, by an enzyme specifically formed or located at the place where the medical device should be positioned. Specifically, the present invention discloses a point of care method and assay for accurately positioning a feeding tube in the stomach of a patient based on detecting the presence of a hydrolase enzyme found in the stomach where the feeding tube should be positioned.
2. Description of the Prior Art
Feeding tubes are medical devices that primarily provide patients with proper nourishment or medication to those who are unable to ingest food or drugs on their own. There are numerous types of feeding tubes available depending on the method of insertion. For example, nasogastric tubes (NG tubes) are inserted through the nose, past the throat, and down into the stomach of patients, whereas orogastric tubes (OG tubes) are inserted through the mouth, past the throat and into the stomach. Gastric tubes (G-tubes) or percutaneous endoscopic gastronomy tubes (PEG tubes) are also available and are inserted into the abdomen via a small incision into the stomach. G-tubes are commonly used for long-term enteral nutrition. Feeding tubes have other uses besides providing nourishment, in that they can also be used to empty and decompress the stomach during surgery. The type of feeding tube desired will vary based on a patient's age and medical condition. The fitting and use of feeding tubes are considered common medical procedures with widespread use. In fact sales figures from the top three nasogastric tube manufacturers estimate that 1.5 billion tubes were sold in 1999 (Hoffman, S. et al., Langenbeck's Arch Surg, 386:402-409 (2001)). Regardless of the method of insertion it is important that feeding tubes are accurately positioned in the stomach of patients.
The positive identification of the placement of a feeding tube in a patient during and after insertion is highly desirable to a high degree of precision and accuracy. Incorrect placement of a feeding tube and subsequent administration of food or drugs can have serious or life threatening consequences for the patient. To ensure safe positioning of feeding tubes during clinical procedures, the distal end of the feeding tube must be positioned within the stomach and not in other locations within the body. Failure to locate the feeding tube in the stomach can result in harm and even death to the patient, particularly if feeding occurs into the lungs. Once a feeding tube is fitted into a patient, frequent placement checks are required to be carried out by a clinician to ensure correct feeding tube placement is maintained. Current recommended clinical guidance dictates that testing should be done before each feeding or when medication is administered, following vomiting, retching or coughing and if there is any indication that the tube displacement may have occurred, e.g., if the tape securing the tube is loose, if the tube is no longer visible or if it is kinked. The mean duration a patient has a nasogastric feeding tube fitted is 5.2 days (Park, R. H. R., BMJ, 304:1406-9 (1992)) and the frequency of the testing should occur several times a day. Therefore, the total number of tests carried out to verify feeding tube placement is extremely high.
Several existing methods for verifying the placement of a feeding tube are known, including those relying on a sample obtained by aspiration (withdrawal of a liquid sample of a patient through the tube following placement). The tests of the sample obtained by aspiration include examining the visual characteristics of the aspirate, pH measurement, laboratory measurements of concentration levels of bilirubin, pepsin and trypsin, and measurement of the carbon dioxide level at the proximal end of the feeding tube. Other tests to confirm correct placement of a feeding tube, not requiring the sampling of liquid, include auscultating for a gurgling sound over the abdomen, measuring the length from the nose to the proximal end of the tube and X-ray examination.
There are conflicting opinions on the reliability, accuracy and precision of verification tests used to confirm feeding tube placement. The widely accepted ‘gold standard’ indication test is by X-ray examination. Although X-ray examination has an excellent success rate, in practice this verification test is not routinely used for every placement check, as a result of the prohibitive cost, impracticality and harm to the patient due to the quantity and frequency by which confirmation tests are recommended to occur. Use of X-ray examination to determine feeding tube placement results in longer periods between feedings, overexposure to X-rays and general discomfort associated with X-ray examinations. During the time delay between X-ray examination and feeding, should tube movement occur, the test is invalidated and the X-ray examination must be repeated. Occasionally even the X-ray test can be misinterpreted if the image is not interpreted correctly by a properly trained professional or if the image is complicated by the status of the patient thus making the identification of the tube or its location less certain. All these factors are detrimental to patient health. In many instances the use of an X-ray examination to carry out this test is simply unavailable outside of hospitals or larger institutions which can offer this service.
Laboratory testing of bilirubin, pepsin and trypsin concentration levels can be a useful indicator to predict feeding tube location, but such methods are not practical for clinical use, particularly for a bedside or point of care setting (Metheny, N. et al., J Parenter Enteral Nutr, 21: 279 (1997)). The implementation of tests involving measuring concentration levels of bilirubin, pepsin and trypsin have not been pursued because of the high number of samples requiring analysis, the requirement for rapid delivery and turnaround of results, the provision of a suitable laboratory facility within close proximity to the patient, the overwhelming volume of testing required and the cost burden that would be incurred to deliver this service. A simple reliable point of care or bedside test is needed to determine accurate placement of a feeding tube in a patient's stomach. In fact, the Department of Health in the United Kingdom has recognized the need to improve bedside testing methods that do not rely on x-ray techniques and is hopeful that in the future such a test will become possible.
(www.haps.bham.ac.uk/publichealth/psrp/documents/PS048_Call_for_proposals_NG_tubes.pdf)
In the absence of a suitably rapid, low cost, convenient, unambiguous and accurate test within a bedside or point of care clinical setting, less accurate methods are sometimes used auscultating for a gurgling sound over the abdomen or visual inspection of the aspirate. These practices involve either combination or multiple testing, such as those outlined above, to try to offset the high risks attributable to the person doing the test based on their clinical experience. Such practices are recognized as problematic and detailed protocols are described to avoid possible complications (http://www.nrls.npsa.nhs.uk/resources/?EntryId45=59794 and Yardley, I. et al., Clinical Medicine, Journal of the Royal College of Physicians, Vol. 10, No. 3: pp. 228-230(2010)).
Another commonly used test to verify correct feeding tube placement is measuring the pH of an aspirate sample from where the feeding tube is placed. The pH of stomach aspirate is generally expected to be lower (more acidic) than aspirate from an incorrectly located feeding tube (e.g., the lungs) due to the presence of gastric acid in the stomach. The reliability provided by a pH test in determining successful placement of the feeding tube is higher than comparable methods available within a clinical bedside environment. But even with this method, there are many instances where this test is unsuitable. This is especially so for those patients whose gastric pH is raised from normal levels by the use of common prescription drugs and medication. Additionally, the normal level of gastric pH is known to vary widely between individuals, depending on several external factors. The pH of the stomach will even vary depending upon the time since the patient's last meal. pH tests are administered by clinical staff using indicator paper. Since the range for gastric aspirate is typically between pH 0 and pH 7 it can make accurate diagnosis difficult and unreliable, owing to the differences in color of the indicator paper across this range. This color differentiation, and hence pH estimation, can also be influenced by external factors such as ambient light and the eyesight of the clinician making the assessment.
Detailed assessments by the Department of Health have been made as to what is a safe acidic pH “cut off” measurement to ensure the tube is correctly positioned within the stomach. In the past litmus paper has been used, but use of the litmus test has recently been criticized for being inaccurate and therefore pH indicator paper should be used in its place. As depicted in Table 1 and FIG. 7, a pH measurement of 4.0 or less results in correct tube placement, but the overall failure rate of the placement tests increases, necessitating additional X-ray tests. Elevating the pH measurement “cut off” to 5.5 enables more tests to indicate stomach placement, thus improving the “pass rate” but with an increased risk that correct location may not be made. Therefore a lower pH “cutoff” (e.g. pH 4.0) is preferable to ensure the best possible patient safety by accurately determining stomach placement, albeit with an increased burden on X-ray use. A preferable option is therefore to use the lower pH cutoff (pH 4.0) but with a test that achieves a high “pass rate”, thereby maintaining patient safety and reducing or avoiding an increase in X-ray confirmation tests.
TABLE 1Outcomes of Clinical GuidelinesPlacementUnnecessaryErrorsX-raypH 5.5 feed; X-ray everyone9.38%24.15%with pH > 5.5pH 4 feed; X-ray everyone0.62%34.05%with pH > 4X-ray everyone0  75%
Currently, misplaced naso or orogastric tubes, not detected prior to use is a significant patient safety issue and was the second most reported preventable patient safety incident in a 2009-2010 United Kingdom National Health Service annual report. Such preventable safety incidents also referred to as “never events”, can lead to hospitals losing important funding. It should be highlighted that the incidence of feeding tubes identified as being misplaced is infrequent. However, although the chance of misplacement is small, owing to the tremendous number of verification tests carried out each year (estimated to be many millions) the absolute number of misplacements is high. Accurate determination of the error rate of existing feeding tube misplacements is difficult to obtain since they are poorly reported and depend on how they are defined. In adults, tube misplacements range is thought to average at 4%, while in children the figure is higher, ranging somewhere between 21-43.5%. Based on the extremely high number of verification tests estimated to be carried out each year, it is clear that robust point of care tests to confirm feeding tube placement are imperative since even though feeding tube misplacement events occur at a low rate with the current usage, they still happen reasonably frequently.
In summary, the results of these practices expose patients fitted with a feeding tube to a high level of risk. The negative outcomes resulting from the misdiagnosis or lack of diagnosis of the feeding tube placement are dire, causing numerous instances of severe harm and death. Consequently, there is a critical need to address the requirements of a suitable simple point of care verification test. The requirements of such a verification test must include the following features: operation at the point of care of a patient, low cost, rapid result, low design complexity, minimal alteration to current practices, excellent reliability and no requirement for the user to comprehend the technical features underpinning the test.
The distal end of the feeding tube must be placed in the stomach and not the lung or the throat. Therefore, the identification of a species or entity which is uniquely present in the stomach and whose use incorporates the desirable features of the feeding tube verification test, as outlined above, is highly desirable. pH is one such indicator and is used in existing tests, but it is associated with a high degree of error and cannot be used in every circumstance. Since the primary physiological function of the stomach is digestion of food, the entities which facilitate digestion are likely to be present at a sufficiently high levels or degree of function or activity to provide sufficient sensitivity required for an improved feeding tube placement test. Those entities that are present exclusively in the stomach provide a route by which a point of care feeding tube placement test could become feasible. The main entities which carry out this digestive role in the stomach are hydrolase enzymes. These occur extensively throughout the stomach and are sub-classified into three main groups: proteases, glycoside hydrolases and lipases/esterases, depending on their mode of action and to which food group they act upon. The products resulting from these enzyme-catalysed chemical reactions offer an opportunity for a suitable detection method. For proteases the resulting products are smaller peptide fragments or amino acids, for glycoside hydrolases the products are smaller carbohydrate fragments or monosaccharides and for lipases/esterases the products are acids and alcohols. Detection of one or more of these products at the bedside using a test, featuring the desirable attributes outlined, would result in a highly desirable feeding tube placement diagnostic test. Critically, the exceptional selectivity associated with enzyme-catalyzed reactions would underpin the reliability and specificity of the test, in direct contrast to the ambiguous tests currently available. The present invention is provided to overcome limitations and drawbacks of the prior art and to provide novel aspects not heretofore available.